This application is to renew a project focused on using mathematical models to understand and predict the emergence of drug resistance to antiretrovirals (ARVs) for the treatment of Human Immunodeficiency Virus (HIV). As the usage rate of ARVs in resource-poor regions is increasing, high levels of drug resistance potentially could emerge and have a devastating impact on public health worldwide, derailing global plans to provide this treatment to many millions of HIV-infected individuals. Our proposed projects will extend the work of the current award, which showed the value of using mathematical models to understand the temporal dynamics of drug-resistant strains of HIV in the United States (US), and for predicting the magnitude of resistance in this setting. In the renewal our work will be extended by combining mathematical modeling with statistical analysis of datasets collected by collaborating groups in the US, Europe and Africa. We will have access to data on drug resistance and important related variables from large scale epidemiological and treatment studies conducted in these three continents. In resource-poor settings, such as Africa, drugs will be limited and thus demand will often greatly exceed supply. We will investigate the problems of allocating ARVs in Africa by using operation research (OR) techniques. We have three Specific Aims. Aim 1: to understand the emergence, explain the present, and predict the evolution of, complex epidemics of drug-resistant strains of HIV in the US and Europe. Aim 2: to predict the evolution of epidemics of drug-resistant strains, as a result of first- line regimens and prophylactic use of ARVs, in Africa. Aim 3: to evaluate the consequences of allocation of scarce HIV healthcare resources in Africa. To achieve this aim we will use models to evaluate the epidemiological and ethical consequences of gender-inequities in access to treatment, assess the epidemiological and ethical impact of treatment priority criteria, and determine healthcare resource allocation strategies that ensure sustainability. Our studies in the renewal will link transmission modeling, OR techniques and statistical analyses; our analyses will take advantage of the extraordinary data sets provided by our collaborators in the US, Europe and Africa. PUBLIC HEALTH RELEVANCE: The emergence and control of drug-resistant strains of HIV is now a global problem. The epidemiology of this problem is complex, and the future of the HIV epidemic is unknown. Our projects focus on using mathematical models to understand, explain, and predict, the evolution of complex epidemics composed of drug-resistant strains of HIV in the US, Europe and Africa. The rollout of antiretrovirals in Africa is just beginning; however demand for drugs greatly exceeds supply. We will, by using mathematical models, evaluate the epidemiological and ethical consequences of allocation of the scarce supply of antiretrovirals in Africa. Our studies are based upon both mathematical modeling and data analyses. Our analyses will take advantage of the extraordinary data sets provided by our collaborators in the US, Europe and Africa. Our results will have direct relevance for health policy makers.